In a functional nucleic acid (for example, siRNA, mRNA or antisense) used in an nucleic acid drug, a protein exhibiting a physiological activity, or a drug, for example, an anticancer drug, the use of carrier has been investigated for the purpose of suppressing degradation due to an enzyme or the like in the living body or delivering the drug tissue-selectively. In particular, since the functional nucleic acid or anticancer drug expresses the activity first after being incorporated into a cell, the use of carrier is essential also in order to enhance the incorporation ability into the cell. As the carrier, a lipid membrane structure, for example, a liposome, a micelle, a vesicle or a lipid fine particle, composed of a phospholipid, a cationic lipid or the like is particularly actively used.
Since the lipid membrane structure is recognized as a foreign matter by the living body, it is trapped by a reticuloendothelial system and discharged rapidly from blood. In contrast, a technique for modifying a surface of the lipid membrane structure with a lipid derivative having bound a hydrophilic polymer of low antigenicity can prolong circulation time of the lipid membrane structure in blood. In particular, since vascular permeability increases on the periphery of tumor tissue in comparison with a normal tissue, it is effective that the lipid membrane structure can be effectively integrated on the periphery of the tumor tissue by extending the circulation time in blood.
On the other hand, it is known that after the lipid membrane structure is transported to the tissue or site as a target, a hydration layer formed by the hydrophilic polymer decreases the interaction with a cell membrane to inhibit in vivo/intracellular kinetics, for example, incorporation into the cell or endosomal escape. As to such a problem, an approach to overcome by detaching the hydrophilic polymer from the lipid membrane structure in an appropriate timing has been made. Most of the strategies utilize an environmental change in each tissue of the living body, for example, reductive environment or the presence of absence of a specific enzyme, as a trigger of the detachment of hydrophilic polymer, and one of them is a technique of utilizing a change in pH.
It is known that the periphery of a tumor tissue in the living body is acidic in comparison with a normal tissue, and the endosomal interior after the drug or the like is introduced into the cell through an endocytosis pathway is also acidic. Therefore, for the purpose of selectively detaching the hydrophilic polymer from the lipid membrane structure under the acidic environment, synthesis examples of a lipid derivative in which a hydrophilic polymer is bound through a linker having acid hydrolyzability have been reported.
For example, in Patent Document 1, hydrolyzability under an acid condition is imparted by introducing a linker having a ketal structure, an acetal structure or an imine structure between polyethylene glycol which is a hydrophilic polymer and a lipid. However, there is no concept on precise control of hydrolysis rate and also data comparing the hydrolysis rate are not indicated.
As another acid-hydrolyzable linker, in Non-Patent Document 1 a hydrazone linker is introduced between polyethylene glycol and a phospholipid. Moreover, although an attempt has been made to control the hydrolysis rate by controlling a number of carbon atoms of a spacer between the hydrazone linker and the phospholipid, a hydrolysis rate under an acid condition (pH 5.5) is constant regardless of the number of carbon atoms of a spacer and it is not possible to precisely control the hydrolysis rate.
Further, in Non-Patent Document 2, kinetics study of the hydrolysis of hydrazone is described and it is shown that in the hydrolysis of hydrazone, the influence of differences in the substituents present on the neighboring benzene ring on the hydrolysis rate is small. Therefore, there is a possibility that the hydrazone is not the best choice for the purpose of controlling the hydrolysis rate.
As described above, although there are many examples of lipid derivatives each having an acid-hydrolyzable linker introduced into the structure for the purpose of detaching the hydrophilic polymer chain under the acidic environment in the living body, there is yet no example of lipid derivative in which a hydrophilic polymer is bound through an acid-hydrolyzable linker which is able to precisely control the hydrolysis rate at an arbitrary pH.